Current research on calcium oxalate stone formation has primarily involved metabolic disorders favoring intratubular calcium oxalate crystallization. However, crystals formed within the tubular lumen are not likely to attain the dimensions required to block a collecting duct and form a microlith during the time it takes for urine to be transported from the glomerulus to the renal pelvis. Therefore, free intraluminal crystals should pass spontaneously through the collecting system of the bladder. An alternate hypothesis for the pathogenesis of renal stones is that the site of initial crystal formation is within the cell. Metochondria possess a great capacity to transport calcium and phosphate. Alterations in mitochondrial calcium transport are seen in nephrocalcinosis and are early indicators of renal cellular injury in a variety of models of acute renal failure. Furthermore, experimental nephrolithiasis is almost invariably accompanied in changes by mitochondrial morphology. It is not known, however, if an alteration in mitochondrial oxalate transport is present in nephrolithiasis or even if renal cortical mitochondria can transport oxalate. In preliminary experiments, we have shown the renal cortical mitochondria accumulated oxalate against an apparent concentration gradient. In an experimental model of calcium oxalate nephrolithiasis induced by feeding rats ammonium oxalate, a change in transmembrane oxalate flux by energized mitochondria clearly preceded mitochondrial swelling and intratubular crystallization. When rats with tubular dysfunction were fed ammonium oxalate, changes in oxalate flux were exaggerated and intracellular crystal formation was detected at levels of oxalate that were innocuous in the absence of tubular dysfunction. The objective of this proposal is to evaluate the role of mitochondrial dysfunction in the pathogenesis of nephrolithiasis. We will examine, in particular, alterations of mitochondrial oxalate and calcium handling and relate these to changes in cellular morphology and proximal tubular function.